NEW ZEALAND DATA SHEET

1. PRODUCT NAME Goserelin, 3.6 mg implant, in a prefilled syringe (Teva)

2. QUALITATIVE AND QUANTITATIVE COMPOSITION One implant contains 3.6 mg goserelin (as goserelin acetate). For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM Implant, in a pre-filled syringe White to off-white cylindrical rods (approximate dimensions: diameter 1.2 mm, length 13 mm, mass 18 mg), embedded in biodegradable polymer matrix.

4. CLINICAL PARTICULARS 4.1 Therapeutic indications Goserelin (Teva) 3.6 mg is indicated for the management of:

• Prostate cancer suitable for hormonal manipulation • Adjuvant and neoadjuvant therapy in combination with radiotherapy for the management of locally advanced prostate cancer in men suitable for hormonal manipulation • Pre- and peri-menopausal women with hormone receptor positive breast cancer suitable for hormonal manipulation • Endometriosis: Goserelin (Teva) alleviates symptoms including pain, and reduces the size and number of endometrial lesions. • Uterine fibroids: Goserelin (Teva) shrinks the lesions, reduces symptoms including pain, and causes cessation of menses in the majority of patients thereby improving haematological status when previous heavy menstrual loss has caused anaemia. • Endometiral thinning: Use as an endometrial thinning agent prior to endometrial ablation. As a prethinning agent, Goserelin (Teva) 3.6 mg should be administered as two implants, four weeks apart, with surgery planned for between zero and two weeks after the second implant injection. • Assisted reproduction: Pituitary down regulation in preparation for superovulation.

4.2 Dose and method of administration Dose Adults One 3.6 mg depot of Goserelin (Teva) injected subcutaneously into the anterior abdominal wall, every 28 days. Use of Goserelin (Teva) in treatment of benign gynaecological conditions should be limited to six months because of possible osteoporotic effects. Adjuvant and/or neoadjuvant therapy in combination with radiotherapy may include short-term use of an anti-androgen to prevent flare. For assisted reproduction, once pituitary down regulation has been achieved with Goserelin (Teva), superovulation and oocyte retrieval should be carried out in accordance with normal practice. Paediatric population Goserelin (Teva) is not indicated in children.

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Special populations No dosage adjustment is necessary for patients with renal or hepatic impairment, or in the elderly. Method of administration Goserelin (Teva) is indicated for subcutaneous use. For correct administration of Goserelin (Teva), refer to instructions printed on inside of carton. Use only if pouch is undamaged. Use immediately after opening pouch. Goserelin (Teva) is administered by subcutaneous injection, according to the following instructions: Remove the applicator from the sterile pack. Check whether the implant is in the intended position in the applicator. Remove the safety ring.

Grip the applicator on the syringe barrel and remove the protective cover.

Press the skin of the patient together while you are comprising the syringe barrel and insert the needle obliquely (almost parallel to the skin). Insert the needle so far into the subcutaneous tissue (not in muscle or into the abdominal cavity) of the anterior abdominal wall under the umbilical line, until the syringe barrel touches the patient's skin. This contact with the skin must remain during the entire application process. Press the syringe plunger down. The implant is transported to the needle tip. Do not pull the syringe back in any case. During the application, the syringe barrel has to touch the skin of the patient.

When the plunger is stopped, the needle retraction is unlocked automatically.

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The needle is retracted from the tissue into the syringe barrel. The syringe barrel must remain in contact with the patient's skin. Normally the plunger movement forward and needle retraction are carried out in one smooth motion. The application process is completed. The needle has been fully retracted into the barrel of the syringe. The supernatant mandrel protects against injury at the needle tip.

4.3 Contraindications Hypersensitivity to the active substance or any of the excipients listed in section 6.1. Pregnancy and lactation.

4.4 Special warnings and precautions for use Goserelin (Teva) 3.6 mg is not indicated for use in children, as safety and efficacy have not been established in this group of patients. Injection site injury has been reported with goserelin administration, including events of pain, haematoma, haemorrhage and vascular injury. Monitor affected patients for signs or symptoms of abdominal haemorrhage. In very rare cases, administration error resulted in vascular injury and haemorrhagic shock requiring blood transfusions and surgical intervention. Extra care should be taken when administering Goserelin (Teva) to patients with a low BMI and/or receiving full anticoagulation medications. The use of Goserelin (Teva) 3.6 mg in men at particular risk of developing ureteric obstruction or spinal cord compression should be considered carefully and the patients monitored closely during the first month of therapy. If spinal cord compression or renal impairment due to ureteric obstruction are present or develop, specific standard treatment of these complications should be instituted. Isolated cases have been reported. Initially Goserelin (Teva), like other LHRH agonists, transiently increases serum testosterone. Some patients may experience a temporary increase in bone pain, which can be managed symptomatically. A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may manifest as diabetes or loss of glycaemic control in those with pre-existing diabetes mellitus. Consideration should therefore be given to monitoring blood glucose. An increased risk of developing myocardial infarction and sudden cardiac death has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease. The use of LHRH agonists may cause a reduction in bone mineral density. In women, current available data suggest that recovery of bone loss occurs on cessation of therapy in the majority. Preliminary data suggest the use of goserelin in combination with tamoxifen in patients with breast cancer may reduce bone mineral loss. In patients receiving goserelin for the treatment of endometriosis, the addition of

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hormone replacement therapy (a daily oestrogenic agent and a progestogenic agent) has been shown to reduce bone mineral density loss and vasomotor symptoms. In men, preliminary data suggest the use of a bisphosphonate in combination with a LHRH agonist may reduce bone mineral loss. Following two years treatment for early breast cancer in women, the average loss of BMD was 6.2% and 11.5% at the femoral neck and lumbar spine respectively. This loss has been shown to be partially reversible at the one year off treatment follow-up with recovery to 3.4% and 6.4% relative to baseline at the femoral neck and lumbar spine respectively. Currently, there are no clinical data on the effects of treating benign gynaecological conditions with Goserelin (Teva) 3.6 mg for periods in excess of six months. Androgen deprivation therapy may prolong the QT interval, although a causal association has not been established with goserelin. In patients with a history of or who have risk factors for QT prolongation and in patients receiving concomitant medicinal products that may prolong the QT interval (see Interaction with other medicinal products and other forms of interaction ) physicians should assess the benefit risk ratio including the potential for Torsade de Pointes prior to initiating Goserelin (Teva). The use of Goserelin (Teva) may cause an increase in cervical resistance and care should be taken when dilating the cervix. Assisted Reproduction Goserelin (Teva) 3.6 mg should only be administered as part of a regimen for assisted reproduction under the supervision of a specialist experienced in the area. As with other LHRH agonists, there have been reports of ovarian hyperstimulation syndrome (OHSS) associated with use of Goserelin (Teva) 3.6 mg in combination with gonadotrophins. The stimulation cycle should be monitored carefully to identify patients at risk of developing OHSS. Human chorionic gonadotrophin (hCG) should be withheld if appropriate. It is recommended that Goserelin (Teva) 3.6 mg be used with caution in assisted reproduction regimens in patients with polycystic ovarian syndrome, as follicle recruitment may be increased. Paediatric Population Goserelin (Teva) is not indicated for use in children, as safety and efficacy have not been established in this patient group.

4.5 Interaction with other medicinal products and other forms of interaction Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Goserelin (Teva) with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated.

4.6 Fertility, pregnancy and lactation Use in pregnancy Goserelin (Teva) should not be used during pregnancy as there is a theoretical risk of abortion or foetal abnormality if LHRH agonists are used during pregnancy. Potentially fertile women should be examined carefully before treatment to exclude pregnancy. Non-hormonal methods of contraception should be employed during therapy until menses is resumed. Pregnancy should be excluded before goserelin is used for assisted reproduction. When goserelin is used in this setting, there is no clinical evidence to suggest a causal association between goserelin and any subsequent abnormalities of oocyte development or pregnancy or outcome.

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Use in lactation The use of Goserelin (Teva) during breastfeeding is not recommended.

4.7 Effects on ability to drive and use machines There is no evidence that goserelin would result in impairment of ability to drive or operate machinery.

4.8 Undesirable effects The following frequency categories for adverse drug reactions (ADRs) were calculated based on reports from goserelin clinical trials and post-marketing sources. The following convention has been used for classification of frequency: Very common (≥ 1/10), Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1,000 to < 1/100), Rare (≥ 1/10,000 to < 1/1,000), Very rare (< 1/10,000) and Not known (cannot be estimated from the available data). Table: Goserelin 3.6 mg adverse drug reactions presented by MedDRA System Organ Class

MedDRA SOC Frequency Males Females Neoplasms, benign Very rare Pituitary tumour Pituitary tumour malignant and unspecified (including Not known N/A Degeneration of uterine cysts and polyps) fibroid

Immune system Uncommon Drug hypersensitivity Drug hypersensitivity disorders Rare Anaphylactic reaction Anaphylactic reaction

Endocrine disorders Very rare Pituitary haemorrhage Pituitary haemorrhage

Metabolism and nutrition Common Glucose tolerance N/A disorders impaireda

Uncommon N/A Hypercalcaemia

Psychiatric disorders Very common Libido decreasedb Libido decreasedb

Common Mood changes, Mood changes, depression depression

Very rare Psychotic disorder Psychotic disorder

Nervous system Common Paraesthesia Paraesthesia disorders Spinal cord compression N/A

N/A Headache

Cardiac disorders Common Cardiac failuref , N/A myocardial infarctionf

Not known QT prolongation QT prolongation

Vascular disorders Very common Hot flushb Hot flushb

Common Blood pressure Blood pressure abnormalc abnormalc

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Skin and subcutaneous Very common Hyperhidrosisb Hyperhidrosisb , acnei tissue disorders Common Rashd Rashd , alopeciag

Not known Alopeciah (see Common)

Musculoskeletal, Common Bone paine N/A connective tissue and bone disorders (see Uncommon) Arthralgia Uncommon Arthralgia (see Common)

Renal and urinary Uncommon Ureteric obstruction N/A disorders

Reproductive system and Very common Erectile dysfunction N/A breast disorders N/A Vulvovaginal dryness

N/A Breast enlargement

Common Gynaecomastia N/A

Uncommon Breast tenderness N/A

Rare N/A Ovarian cyst

N/A Ovarian hyperstimulation syndrome (if concomitantly used with gonadotrophins)

Not known N/A Withdrawal bleeding

General disorders and Very common (see Common) Injection site reaction administration site conditions Common Injection site reaction (see Very common) N/A Tumour flare, tumour pain (on initiation of treatment)

Investigations Common Bone density decreased, Bone density decreased, weight increased weight increased

a A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may manifest as diabetes or loss of glycaemic control in those with pre-existing diabetes mellitus. b These are pharmacological effects which seldom require withdrawal of therapy. c These may manifest as hypotension or hypertension, have been occasionally observed in patients administered goserelin. The changes are usually transient, resolving either during continued therapy or after cessation of therapy with goserelin. Rarely, such changes have been sufficient to require medical intervention, including withdrawal of treatment from goserelin. d These are generally mild, often regressing without discontinuation of therapy. e Initially, prostate cancer patients may experience a temporary increase in bone pain, which can be managed symptomatically. f Observed in a pharmaco-epidemiology study of LHRH agonists used in the treatment of prostate cancer. The risk appears to be increased when used in combination with anti-androgens. g Loss of head hair has been reported in females, including younger patients treated for benign conditions. This is usually mild but occasionally can be severe. h Particularly loss of body hair, an expected effect of lowered androgen levels. i In most cases acne was reported within one month after the start of goserelin.

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Reduction in glucose tolerance, manifesting as diabetes or loss of glycaemic control in those with pre- existing diabetes, has been reported during treatment with GnRH agonists including Goserelin (Teva) (see Special warnings and precautions for use). A small increased risk of developing myocardial infarction and sudden cardiac death has been reported in association with use of GnRH agonists in men.

4.9 Overdose There is limited experience of overdosage in humans. In cases where goserelin has unintentionally been re-administered early or given at a higher dose, no clinically relevant adverse effects have been seen. Animal tests suggest that no effect other than the intended therapeutic effects on sex hormone concentrations and on the reproductive tract will be evident with higher doses of goserelin. If overdosage occurs, this should be managed symptomatically. For information on the management of overdose, contact the New Zealand Poison Information Centre on 0800 POISON or 0800 764 766.

5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: hormones and related agents, ATC code: L02AE03 Goserelin (D-Ser(But)6 Azgly10 LHRH) is a synthetic analogue of naturally occurring LHRH. On chronic administration goserelin results in inhibition of pituitary LH secretion leading to a fall in serum testosterone concentrations in males and serum estradiol concentrations in females. This effect is reversible on discontinuation of therapy. Initially, goserelin, like other LHRH agonists, may transiently increase serum testosterone concentration in men and serum estradiol concentration in women. In men, by around 21 days after the first depot injection, testosterone concentrations have fallen to within the castrate range and remain suppressed with continuous treatment every 28 days. This inhibition leads to prostate tumour regression and symptomatic improvement in the majority of patients. In the management of patients with metastatic prostate cancer, goserelin has been shown in comparative clinical trials to give similar survival outcomes to those obtained with surgical castrations. In a combined analysis of 2 randomised controlled trials comparing bicalutamide 150 mg monotherapy versus castration (predominantly in the form of goserelin), there was no significant difference in overall survival between bicalutamide-treated patients and castration-treated patients (hazard ratio = 1.05 [CI 0.81 to 1.36]) with locally advanced prostate cancer. However, equivalence of the two treatments could not be concluded statistically. In comparative trials, goserelin has been shown to improve disease-free survival and overall survival when used as an adjuvant therapy to radiotherapy in patients with high-risk localised (T1-T2 and PSA of at least 10 ng/ml or a Gleason score of at least 7), or locally advanced (T3-T4) prostate cancer. The optimum duration of adjuvant therapy has not been established; a comparative trial has shown that 3 years of adjuvant goserelin gives significant survival improvement compared with radiotherapy alone. Neo-adjuvant goserelin prior to radiotherapy has been shown to improve disease-free survival in patients withhigh risk localised or locally advanced prostate cancer. After prostatectomy, in patients found to have extra-prostatic tumour spread, adjuvant goserelin may improve disease-free survival periods, but there is no significant survival improvement unless patients have evidence of nodal involvement at time of surgery. Patients with pathologically staged locally advanced disease should have additional risk factors such as PSA of at least 10 ng/ml or a Gleason score of at least 7 before adjuvant goserelin should be considered. There is no evidence of improved clinical outcomes with use of neo-adjuvant goserelin before radical prostatectomy.

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In women, serum estradiol concentrations are suppressed by around 21 days after the first depot injection and, with continuous treatment every 28 days, remain suppressed at levels comparable with those observed in postmenopausal women. This suppression is associated with a response in hormone- dependent advanced breast cancer, uterine fibroids, endometriosis and suppression of follicular development within the ovary. It will produce endometrial thinning and will result in amenorrhoea in the majority of patients. During treatment with LHRH analogues patients may enter the menopause. Rarely, some women do not resume menses on cessation of therapy. Goserelin in combination with iron has been shown to induce amenorrhoea and improve haemoglobin concentrations and related haematological parameters in women with fibroids who are anaemic. The combination produced a mean haemoglobin concentration 1 g/dl above that achieved by iron therapy alone.

5.2 Pharmacokinetic properties The bioavailability of goserelin is almost complete. Administration of a depot every four weeks ensures that effective concentrations are maintained with no tissue accumulations. Goserelin is poorly protein bound and has a serum elimination half-life of two to four hours in subjects with normal renal function. The half-life is increased in patients with impaired renal function. For the compound given monthly in a depot formulation, this change will have minimal effect. Hence, no change in dosing is necessary in these patients. There is no significant change in pharmacokinetics in patients with hepatic failure.

5.3 Preclinical safety data Following long-term repeated dosing with goserelin, an increased incidence of benign pituitary tumours has been observed in male rats. Whilst this finding is similar to that previously noted in this species following surgical castration, any relevance to man has not been established. In mice, long-term repeated dosing with multiples of the human dose, produced histological changes in some regions of the digestive system manifested by pancreatic islet cell hyperplasia and a benign proliferative condition in the pyloric region of the stomach, also reported as a spontaneous lesion in this species. The clinical relevance of these findings is unknown.

6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Poly(D,L-lactide-co-glycolide) 50:50

6.2 Incompatibilities Not applicable.

6.3 Shelf life Prior to first opening: 48 months After first opening: The product should be used immediately after opening of the pouch.

6.4 Special precautions for storage Store below 30oC. Store in the original package in order to protect from moisture and light.

6.5 Nature and contents of container Pack size: 1 implant per pack. Each pack contains a single dose prefilled syringe consisting of three main parts: the body with the implant holder unit, a mandrin and a needle unit. The implant in a prefilled syringe is packed together with a desiccant capsule in a pouch within a cardboard carton.

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6.6 Special precautions for disposal No special requirements for disposal.

7. MEDICINE SCHEDULE Prescription Medicine

8. SPONSOR Teva Pharma (New Zealand) Limited PO Box 128 244 Auckland, New Zealand Telephone: 0800 800 097

9. DATE OF FIRST APPROVAL 19 July 2018

10. DATE OF REVISION OF THE TEXT 28 April 2021

SUMMARY TABLE OF CHANGES

Section changed Summary of new information 4.2 Instructions for use added.

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